The long-term goal of this research is to investigate the mechanisms of spontaneous obesity in mice. Previous work has identified 4 chromosomal regions (mouse chr. 6,7,12,and 15) or loci (QTLs) that contribute to obesity in spontaneously obese BSB mice. BSB mice were produced by a backcross of (Mus spretus x C57BL/6J) F1 x B6. Preliminary data on an available congenic mouse strains confirm that the locus on chr. 7 affects adiposity. The objective of this present proposal is to identify the genes underlying these obesity loci. Congenic mouse strains carrying the spretus chromosomal regions as donor DNA on the B6 background will be created. As co-incident QTLs for obesity, plasma cholesterol and hepatic lipase (HL) activity on mouse chr. 7 were found, the already constructed B6 HL knockout will used to test the hypothesis that alterations of HL activity determine these cholesterol and/obesity loci. BSB backcrosses with the HL KO B6 mouse will yield animals both homozygous and heterozygous for the HL knock-out. QTLs at chromosome 7; will be compared and contrasted in these two groups. The mouse chr. 6,7, and 1 loci include within their 90 percent confidence intervals, respectively, the obese, tubby, and uncoupling protein 2-genes. Molecular and biochemical studies of these candidate genes will be performed to test whether differences are likely to explain the observed effect on the trait. If there are differences in the coding portion of the spretus and B6 leptin, then the biological consequence of the differences will be tested. The chromosome 6 locus was linked to just one of the four fat pads measured in BSB mice. Leptin mRNA levels in the four fat pads will be determined to examine their correlations with plasma leptin and fat pad sizes. They have already found that spretus and B6 UCP2 differ for 2 amino acids, so uncoupling activity of UCP2 from these strains will be examined.